Life Extension®
immediately recognized errors in this anti-testosterone study that render its findings meaningless.

This study was designed by physicians who apparently don’t know how to safely restore testosterone levels in aging men.

The media’s portrayal of this flawed study will discourage aging men from properly restoring their testosterone levels. To help spare the lives of
testosterone deficient men, we have prepared an extensive rebuttal to this erroneous report.

Life Extension’s
official response, starting below provides a detailed point-by-point rebuttal to the many defects in this study that was used to discredit natural
testosterone restoration.

Below is a brief summary of the more serious flaws that generated the media frenzy.

In order to confer the most protection against heart disease, total testosterone blood levels need to be raised higher than 500–550ng/dL.4 Life Extension believes that optimal youthful total testosterone is in the 700–900ng/dL range.

The men enrolled in this flawed study only boosted their mean total testosterone levels to 332ng/dL.5 Previous studies show this low testosterone level (332 ng/dL) is associated with an increased heart attack risk compared with levels above 500–550ng/dL.4

The men in this study were not properly individually dosed and monitored, which explains why the testosterone treatment they received failed to
restore their blood testosterone levels to anywhere near cardio-protective ranges.4,5

Estradiol
(an estrogen) blood levels were not reported in this study used to discredit testosterone drugs. A subset of aging men, often with increased
visceral body fat (body fat around the internal organs of the abdominal cavity), have a tendency to convert testosterone into excess estrogen.6,7 This excess estrogen may alter the balance of anticoagulant and procoagulant (clotting) factors in the blood, and potentially enhance the
risk of heart attack and stroke.8-11 Any man treated with testosterone drugs should also have his estradiol blood level tested
to ensure that the testosterone is not excessively converting to estrogen. If estradiol increases excessively, then low-dose aromatase-inhibiting drugs
(such as 1 mg/week of anastrozole [Arimidex®]) can be prescribed to reduce the conversion of testosterone to estrogen.12

A subgroup of overweight men with excess visceral body fat treated with testosterone in this study would be expected to excessively convert (aromatize)
their testosterone into estrogen, which may help explain why more men in the testosterone group suffered a greater percentage of heart attacks.

Research published in recent years shows profound cardiovascular benefits in response to higher testosterone levels (in men).4,13,14 The media
conveniently ignored these positive reports and narrowly focused on the egregiously flawed study published in the Journal of the American Medical Association (JAMA).

Based on many published studies, Life Extension has recommended for decades that aging men restore testosterone to a youthful
range. We’ve always warned that for some men, restoring one’s testosterone to more youthful levels could create excessive levels of estrogen, which is
readily detectable by blood testing and reversible using aromatase-inhibiting therapies.

What’s most frightening is that most mainstream doctors today are blindly prescribing testosterone drugs and omitting any kind of estrogen testing. This
creates a very dangerous environment for men who convert their testosterone into excess estrogen!

A number of studies show that testosterone replacement therapy improves multiple measures of men’s vitality, especially related to cardio-metabolic health.4,15-24

Therefore, on November 5, 2013, we were startled to see media headlines like “Testosterone Treatments Linked to Heart Risks.”1-3

This headline and others like it were prompted by a retrospective, observational study in the September 5, 2013, issue of the Journal of the American MedicalAssociation (JAMA). The study suggests testosterone therapy may increase risk of death and
certain cardiovascular events.5

There are several significant shortcomings in the study’s design and methodology, and the results conflict with an existing body of research showing that low testosterone increases a man’s risk of heart problems.

Woefully Inadequate Testosterone Replacement

The goal of testosterone restoration in most cases is to restore youthful blood levels of the hormone. Typically, Life Extension suggests men target a
blood level of testosterone between 700 and 900 ng/dL for optimal health.

In studies designed to assess the impact of testosterone replacement therapy, one of the most important considerations is to measure subjects’ blood levels
of testosterone regularly throughout the study period. This allows the scientists conducting the study to make sure subjects are taking their testosterone
as directed and that their blood levels are rising as expected.

Unbelievably, in the flawed analysis published in JAMA, only 60% of study subjects receiving testosterone had a
follow-up blood test to assess their testosterone levels. Among them, average testosterone levels rose from a very low level of 175.5 ng/dL at baseline to a still far-from-optimal level of 332.2 ng/dL during testosterone therapy.

Raising testosterone levels from a paltry 175.5 ng/dL to only 332.2 ng/dL is unlikely to deliver robust health benefits.
In fact, research has shown that restoring testosterone levels to 500 ng/dL or higher is associated with pronounced health benefits,
whereas benefits may be less evident at lower levels.4,19

Failure To Account For Impact Of Estrogen

One of the biggest perils facing aging men is the conversion of their testosterone into estrogen by aromatase.25

Aromatase is an enzyme that converts testosterone and other androgens into estrogen, primarily estradiol. Although some conversion of testosterone to
estradiol is essential for health, too much conversion can have devastating consequences for men.

In one study, men with heart failure and high levels of estradiol had an increased risk of death compared to men whose levels of estradiol were in a
balanced, middle range of 21.8–30.1 pg/mL.26 These findings support Life Extension’s long held suggested optimal estradiol
level of 20-30 pg/mL. Moreover, excess estrogen promotes abnormal clot formation,9 and high levels may be associated with an
increased risk of stroke.10

When men take testosterone, there is a significant propensity for it to be converted into estradiol by aromatase; this is especially so for aging men.27 It is therefore important that men undergoing testosterone therapy monitor their estradiol levels regularly and take steps like using an
aromatase-inhibiting drug to keep estradiol levels in the optimal range in order to protect against the health detriments of excess estrogen.

In the paper published by JAMA (Journal of the American Medical Association), there was no report of the subjects’ estradiol levels. If
estradiol was not monitored during testosterone administration, this oversight means that the men receiving testosterone could have experienced a
concurrent rise in estradiol levels. This may have compromised their cardiovascular health and could partially account for the increased risk observed in
the testosterone-treated group.

What You Need to Know

Flawed Media Reports Of Anti-Testosterone Study

The precipitous decline of men’s testosterone levels over the years is inevitable.

Major news media outlets reported that testosterone replacement therapy is linked to heart risk based on a retrospective, observational study that was
published in the September 5, 2013, issue of the Journal of the American Medical Association (JAMA).

In spite of several significant shortcomings in the study’s design and methodology, and results that are in conflict with an existing body of research,
the study suggests adverse effects from testosterone drug therapy.

Over the years, several studies have shown that testosterone replacement therapy improves multiple measures of men’s vitality, especially related to
cardio-metabolic health.

If aging men do not replace their diminishing testosterone, they could succumb to any of the numerous health problems linked to low testosterone
levels: frailty, muscle loss, weight gain, impaired cognition, fatigue, loss of self-confidence, depression, declining bone health, increased risk of
type II diabetes, stroke, and cardiovascular disease.

Significant Difference In Baseline Testosterone Levels Between Groups

Among the men in this JAMA study, there was a statistically significant difference in baseline testosterone levels between the “testosterone
therapy” (treatment) and “no-testosterone” (control) groups.

Among the control group, testosterone levels were higher at baseline (206.5 ng/dL), whereas the average level was significantly lower at
baseline (175.5 ng/dL) for those who received a prescription for testosterone.

The treatment group may have had significantly lower levels of testosterone than the control group for years prior to entering the study. The damage caused
by years of potentially lower testosterone levels was not accounted for in the study and may have skewed the results.

Testosterone restoration is an important step aging men can take to retain good health.

In a revealing study, researchers identified 2,416 men (aged 69-81 years) who were not on any kind of testosterone-affecting treatment. These men were
subjected to a battery of blood tests that included total testosterone and estradiol.

The first observation was that men with increasing levels of testosterone had a decreased prevalence of diabetes, hypertension, and body
fat mass. Compared to men with the highest testosterone levels, those with low testosterone were twice as likely to have a history of
cardiovascular disease. It was also observed that men with the highest testosterone levels were the most physically active.4

This large group of men was followed for an average of 5.1 years. Men in the highest quartile of total testosterone (above 550 ng/dL) had
a 30% lower risk of cardiovascular events. Any level of total testosterone below 550 ng/dL resulted in
significantly increased risk, thus helping establish a minimal baseline as to where total testosterone should be to guard against heart attack or
stroke.

Estradiol levels measured in this group appeared to be mostly in safe ranges and did not impact incidence of cardiovascular events.

Data was tabulated based on hospital reports and/or death certificates for:

Acute myocardial infarction (heart attack)

Unstable angina (chest discomfort caused by a lack of oxygen flow to the heart)

Revascularization procedure (bypass surgery or stenting)

Transient ischemic attack (mini-stroke)

Stroke

The four quartiles of total testosterone in this large group of older men were:

Quartile 1: Total testosterone below 340 ng/dL

Quartile 2: Total testosterone between 341 and 438 ng/dL

Quartile 3: Total testosterone between 439 and 549 ng/dL

Quartile 4: Total testosterone above 550 ng/dL

Of interest was the finding that Quartiles 1, 2, and 3 had about the same risk of cardiac adverse events. It was only in Quartile 4 (when total
testosterone exceeded 550 ng/dL) that the 30% reduction in cardiovascular events occurred.

This finding showed that it did not matter if these men’s total testosterone was very low (below 340 ng/dL) or moderately low (up to 549 ng/dL)…they all had a similar increased risk for suffering a cardiovascular event. Only when total testosterone exceeded 550 ng/dL did cardiovascular risk plummet.

This finding remained consistent for cerebrovascular disease incidence, where men with the highest total testosterone (Quartile 4) had a 23% reduced risk of transient ischemic attack or full blown stroke. The researchers noted this association with reduced cerebrovascular
risk remained after adjustment for traditional risk factors.

The conclusions by the researchers who conducted this study were:

“Higher serum testosterone levels are associated with a reduced risk of fatal and non-fatal cardiovascular events in community dwelling elderly
men.”
4

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